CIGB-258 通过增强高密度脂蛋白稳定性和功能对瘫痪斑马鱼羧甲基赖氨酸急性毒性的抗炎活性。
Anti-Inflammatory Activity of CIGB-258 against Acute Toxicity of Carboxymethyllysine in Paralyzed Zebrafish via Enhancement of High-Density Lipoproteins Stability and Functionality.
机构信息
Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Korea.
LipoLab, Yeungnam University, Gyeongsan 38541, Korea.
出版信息
Int J Mol Sci. 2022 Sep 4;23(17):10130. doi: 10.3390/ijms231710130.
Background: Hyperinflammation is frequently associated with the chronic pain of autoimmune disease and the acute death of coronavirus disease (COVID-19) via a severe cytokine cascade. CIGB-258 (Jusvinza®), an altered peptide ligand with 3 kDa from heat shock protein 60 (HSP60), inhibits the systemic inflammation and cytokine storm, but the precise mechanism is still unknown. Objective: The protective effect of CIGB-258 against inflammatory stress of N-ε-carboxymethyllysine (CML) was tested to provide mechanistic insight. Methods: CIGB-258 was treated to high-density lipoproteins (HDL) and injected into zebrafish and its embryo to test a putative anti-inflammatory activity under presence of CML. Results: Treatment of CML (final 200 μM) caused remarkable glycation of HDL with severe aggregation of HDL particles to produce dysfunctional HDL, which is associated with a decrease in apolipoprotein A-I stability and lowered paraoxonase activity. Degradation of HDL3 by ferrous ions was attenuated by a co-treatment with CIGB-258 with a red-shift of the Trp fluorescence in HDL. A microinjection of CML (500 ng) into zebrafish embryos resulted in the highest embryo death rate, only 18% of survivability with developmental defects. However, co-injection of CIGB-258 (final 1 ng) caused the remarkable elevation of survivability around 58%, as well as normal developmental speed. An intraperitoneal injection of CML (final 250 μg) into adult zebrafish resulted acute paralysis, sudden death, and laying down on the bottom of the cage with no swimming ability via neurotoxicity and inflammation. However, a co-injection of CIGB-258 (1 μg) resulted in faster recovery of the swimming ability and higher survivability than CML alone injection. The CML alone group showed 49% survivability, while the CIGB-258 group showed 97% survivability (p < 0.001) with a remarkable decrease in hepatic inflammation up to 50%. A comparison of efficacy with CIGB-258, Infliximab (Remsima®), and Tocilizumab (Actemra®) showed that the CIGB-258 group exhibited faster recovery and swimming ability with higher survivability than those of the Infliximab group. The CIGB-258 group and Tocilizumab group showed the highest survivability, the lowest plasma total cholesterol and triglyceride level, and the infiltration of inflammatory cells, such as neutrophils in hepatic tissue. Conclusion: CIGB-258 ameliorated the acute neurotoxicity, paralysis, hyperinflammation, and death induced by CML, resulting in higher survivability in zebrafish and its embryos by enhancing the HDL structure and functionality.
背景
细胞因子级联反应导致自身免疫性疾病的慢性疼痛和冠状病毒病（COVID-19）的急性死亡，常伴有炎症过度活跃。CIGB-258（Jusvinza®）是一种源自热休克蛋白 60（HSP60）的 3 kDa 改变肽配体，可抑制全身炎症和细胞因子风暴，但确切机制仍不清楚。目的：测试 CIGB-258 对 N-ε-羧甲基赖氨酸（CML）炎症应激的保护作用，以提供机制见解。方法：将 CIGB-258 处理至高密度脂蛋白（HDL）并注入斑马鱼及其胚胎中，以在存在 CML 的情况下测试其潜在的抗炎活性。结果：CML（终浓度 200 μM）处理导致 HDL 严重糖化，HDL 颗粒严重聚集，产生功能失调的 HDL，这与载脂蛋白 A-I 稳定性降低和对氧磷酶活性降低有关。用亚铁离子降解 HDL3 的作用被 CIGB-258 的共同处理减弱，HDL 中的色氨酸荧光发生红移。将 CML（500 ng）微注射到斑马鱼胚胎中会导致胚胎死亡率最高，只有 18%的存活率和发育缺陷。然而，共同注射 CIGB-258（终浓度 1 ng）可使存活率显著升高至 58%左右，同时发育速度正常。向成年斑马鱼腹腔内注射 CML（终浓度 250 μg）会导致神经毒性和炎症引起的急性瘫痪、突然死亡和躺在笼子底部无法游泳。然而，共同注射 CIGB-258（1 μg）可使游泳能力更快恢复，存活率高于单独注射 CML。单独 CML 组的存活率为 49%，而 CIGB-258 组的存活率为 97%（p < 0.001），肝炎症减少了 50%。与 CIGB-258、英夫利昔单抗（Remsima®）和托珠单抗（Actemra®）的疗效比较表明，CIGB-258 组的恢复和游泳能力更快，存活率高于英夫利昔单抗组。CIGB-258 组和托珠单抗组的存活率最高，血浆总胆固醇和甘油三酯水平最低，肝组织中浸润的炎症细胞（如中性粒细胞）也最少。结论：CIGB-258 通过增强 HDL 结构和功能，改善了 CML 引起的急性神经毒性、瘫痪、炎症过度活跃和死亡，从而提高了斑马鱼及其胚胎的存活率。
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